Overlapping central and peripheral nervous system syndromes in MOG antibody-associated disorders

Abstract

Objective: Antibodies to myelin oligodendrocyte glycoprotein (MOG) are associated with CNS demyelination inclusive of optic neuritis (ON) and transverse myelitis (TM). To examine whether peripheral nervous system (PNS) involvement is associated with MOG antibody-associated disorders (MOGAD), we performed detailed characterization of an Australasian MOGAD cohort.

Methods: Using a live cell-based assay, we diagnosed 271 adults with MOGAD (2013-2018) and performed detailed clinical and immunologic characterization on those with likely PNS involvement.

Results: We identified 19 adults with MOGAD and PNS involvement without prior TM. All patients had CNS involvement including ON (bilateral [n = 3], unilateral [n = 3], and recurrent [n = 7]), a cortical lesion (n = 1), meningoencephalitis (n = 1), and subsequent TM (n = 4). Clinical phenotyping and neurophysiology were consistent with acute inflammatory demyelinating polyneuropathy (n = 1), myeloradiculitis (n = 3), multifocal motor neuropathy (n = 1), brachial neuritis (n = 2), migrant sensory neuritis (n = 3), and paresthesia and/or radicular limb pain (n = 10). Onset MRI spine was consistent with myeloradiculitis with nerve root enhancement in 3/19 and normal in 16/19. Immunotherapy resulted in partial/complete PNS symptom resolution in 12/15 (80%) (steroids and/or IV immunoglobulin n = 9, rituximab n = 2, and plasmapheresis n = 1). We identified serum antibodies targeting neurofascin 155, contactin-associated protein 2, or GM1 in 4/16 patients with MOGAD PNS compared with 0/30 controls (p = 0.01). There was no binding to novel cell surface antigens using an in vitro myelinating sensory neuronal coculture model.

Conclusions: Myeloradiculitis, combined central and peripheral demyelination syndromes, and inflammatory neuropathies may be associated with MOGAD and may be immunotherapy responsive. We identified a subgroup who may have pathology mediated by coexistent autoantibodies.

Figure 1. The clinical, neurophysiological, and radiological characterization of PNS involvement in MOGAD

(A) Clinical phenotyping of the number of CNS episodes in patients in this cohort. ON, inclusive of both BON and UON presentations, was the most frequent clinical phenotype, making up 39/47 (83%) episodes. (B) The right median nerve motor response (white) is smaller than the left (red) with a further reduction of amplitude at the elbow and with reduced persistence of median nerve F wave responses. These findings are consistent with right median neuropathy with conduction block at the elbow in a patient diagnosed with MMN. (C) Axial T1-weighted MRI with gadolinium showing enhancement of dorsal and ventral nerve roots (white arrows). (D) Sagittal T1-weighted MRI with gadolinium showing expansion of the conus (white arrow). (E) Axial fat-suppressed T1 with gadolinium showing enhancement of intradural right S1 nerve root (white arrow). (F) Proportion of the PNS syndromes identified in this cohort of patients with MOGAD. (G) A summary of the immunotherapy responsiveness of particular PNS syndromes—complete resolution occurred in 3/15 patients in whom immunotherapy was trialed (2 with myeloradiculitis and 1 with multifocal motor neuropathy), with 9/15 having only partial resolution and 3/15 being unresponsive to immunotherapy. AIDP = acute inflammatory demyelinating polyneuropathy; BON = bilateral optic neuritis; CIDP = chronic inflammatory demyelinating polyneuropathy; LETM = longitudinally extensive transverse myelitis; MMN = multifocal motor neuropathy; MOG = myelin oligodendrocyte glycoprotein; ON = optic neuritis; PNS = peripheral nervous system; sTM = short transverse myelitis; UON = unilateral optic neuritis.

Figure 2. Antibody-associated peripheral nerve involvement

(A) Human IgG binding (green) colocalizes on the cell surface of HEK293 cells to binding of a commercial pan-neurofascin antibody (red) when cells were incubated with sera from an NF155 positive control and MOGAD PNS patient 5, but not in a healthy control. (B) Human IgG binding (red) colocalizes on the cell surface of HEK293 cells transfected with CASPR2-eGFP (green) when cells were incubated with sera from a CASPR2-positive control and MOGAD PNS patient 8, but not in a healthy control. (C) Images of serum-treated myelinating cocultures labeled with anti-human IgG antibodies (green). Anti-NF200 (blue) and anti-MBP (red) primary antibodies were used to visualize axonal processes and myelin internodes, respectively. This coculture, treated with serum from a healthy control, anti-CNTN1 antibody or anti-NF155 antibody positive controls, and a representative MOGAD PNS patient are shown. Arrows indicate the nodal/paranodal deposition of human IgG. Note lack of specific labeling in healthy control and MOGAD PNS patient serum. CASPR2 = contactin-associated protein-like 2; CNTN1 = contactin 1; DAPI 4′,6-diamidino-2- phenylindole; eGFP = enhanced green fluorescent protein; IgG = immunoglobulin G; MBP = myelin basic protein; MOGAD = myelin oligodendrocyte glycoprotein antibody–associated disorder; NF = neurofascin; NF155 = neurofascin 155; NF200 = neurofilament 200; PNS = peripheral nervous system.